Novel Diagnostic Biomarker BST2 Identified by Integrated Transcriptomics Promotes the Development of Endometriosis via the TNF-α/NF-κB Signaling Pathway.

Endometriosis (EMS) is a common gynecological condition with apparent heterogeneity, lack of diagnostic markers, and unclear pathogenesis. A series of bioinformatics methods were employed to explore EMS's pathological mechanisms and potential biomarkers by analyzing the combined datasets of EMS (GSE7305, GSE7307, GSE58198, E-MTAB-694), which included 34 normal, 127 eutopic, and 46 ectopic endometrium samples. Then, wet-laboratory experiments (including Western blot, qRT-PCR, and Immunohistochemistry, Immunofluorescence, CCK-8, EdU, Wound healing, Transwell, and Adhesion assays) were applied to examine the biomarkers' expression and function in primary endometrial stromal cells. Bioinformatic analysis indicated that the core pathogenesis of EMS was dysregulated immune-inflammation and tissue remolding processes. Among the upregulated DEGs, BST2 was screened as a potential diagnostic biomarker in EMS, which associated with the revised American Fertility Society (r-AFS) stage and immune-inflammation processes of EMS. Moreover, BST2's overexpression was affirmed in the RNA and protein levels in EMS tissues. In vitro experiments demonstrated that TNF-α promoted the expression of BST2 in ESCs. And BST2 knockdown inhibited migration, invasion, adhesion, and inflammation except for the proliferation of ESCs, probably via the TNF-α/NF-κB pathway. Through a combination of wet and dry studies, we concluded that the core pathogenesis of endometriosis was dysregulated immune-inflammation and tissue remolding, and BST2 might be a potential diagnostic and therapeutic target in endometriosis.

Omentum provides a special cell microenvironment for ovarian cancer.

BACKGROUND: Ovarian cancer seriously threatens women's health because of its poor prognosis and high mortality. Due to the lack of efficient early detection and screening methods, when patients seek doctors' help with complaints of abdominal distension, back pain and other nonspecific signs, the clinical results always hint at the widespread metastasis of disease. When referring to the metastasis of this disease, the omentum always takes precedence. RECENT FINDINGS: The distinguishing feature of the omentum is adipose tissue, which satisfies the energy demand of cancer cells and supplies a more aggressive environment for ovarian cancer cells. In this review, we mainly focus on three important cell types: adipocytes, macrophages, and mesenchymal stem cells. Besides, several mechanisms underlying cancer-associated adipocytes (CAA)-facilitated ovarian cancer cell development have been revealed, including their capacities for storing lipids and endocrine function, and the release of hormones, growth factors, and adipokines. Blocking the reciprocity among cancer cells and various cells located on the omentum might contribute to ovarian cancer therapy. The inhibition of hormones, growth factors and adipokines produced by adipocytes will be a novel therapeutic strategy. However, a sufficient number of trials has not been performed. In spite of this, the therapeutic potential of metformin and the roles of exercise in ovarian cancer will be worth mentioning. CONCLUSION: It is almost impossible to overcome completely ovarian cancer at the moment. What we can do is trying our best to improve these patients' prognoses. In this process, adipocytes may bring promising future for the therapy of ovarian cancer.

A novel DNA methylation-related gene signature for the prediction of overall survival and immune characteristics of ovarian cancer patients.

BACKGROUND: Ovarian cancer (OC) is one of the most life-threatening cancers affecting women worldwide. Recent studies have shown that the DNA methylation state can be used in the diagnosis, treatment and prognosis prediction of diseases. Meanwhile, it has been reported that the DNA methylation state can affect the function of immune cells. However, whether DNA methylation-related genes can be used for prognosis and immune response prediction in OC remains unclear. METHODS: In this study, DNA methylation-related genes in OC were identified by an integrated analysis of DNA methylation and transcriptome data. Prognostic values of the DNA methylation-related genes were investigated through least absolute shrinkage and selection operator (LASSO) and Cox progression analyses. Immune characteristics were investigated by CIBERSORT, correlation analysis and weighted gene co-expression network analysis (WGCNA). RESULTS: Twelve prognostic genes (CA2, CD3G, HABP2, KCTD14, PI3, SERPINB5, SLAMF7, SLC9A2, STC2, TBP, TREML2 and TRIM27) were identified and a risk score signature and a nomogram based on prognostic genes and clinicopathological features were constructed for the survival prediction of OC patients in the training and two validation cohorts. Subsequently, the differences in the immune landscape between the high- and low-risk score groups were systematically investigated. CONCLUSIONS: Taken together, our study explored a novel efficient risk score signature and a nomogram for the survival prediction of OC patients. In addition, the differences of the immune characteristics between the two risk groups were clarified preliminarily, which will guide the further exploration of synergistic targets to improve the efficacy of immunotherapy in OC patients.

Dissecting the heterogeneities of the tumor microenvironment between metastatic and nonmetastatic primary colorectal cancer patients by single-cell RNA sequencing.

AIMS: One of the main factors hampering the long-term prognosis of colorectal cancer (CRC) patients is distant metastasis. However, the driving factors of CRC metastasis have not been clarified at the single-cell level, which limits the in-depth study of accurate prediction and prevention of CRC metastasis to improve the prognosis. MATERIALS AND METHODS: Heterogeneities in the tumor microenvironment (TME) between metastatic and nonmetastatic CRC were investigated by single-cell RNA (scRNA) sequencing data. In detail, 50,462 single cells from 20 primary CRC samples, including 40,910 cells from nonmetastatic CRC (M0 group) and 9552 cells from metastatic CRC (M1 group), were systematically analyzed in this study. KEY FINDINGS: Based on the single-cell atlas, we revealed that cancer cells and fibroblasts accounted for relatively high proportions in metastatic CRC compared with nonmetastatic CRC. Moreover, two specific cancer cell subtypes (FGGY+SLC6A6+ and IGFBP3+KLK7+ cancer cells) and three specific fibroblast subtypes (ADAMTS6+CAPG+, PIM1+SGK1+ and CA9+UPP1+ fibroblasts) in metastatic CRC were identified. The functional and differentiation characteristics of these specific cell subclusters were elucidated by enrichment and trajectory analyses. SIGNIFICANCE: These results provide fundamental knowledge for future in-depth research to screen effective methods and drugs to predict and prevent CRC metastasis to improve prognosis.

Linc-ROR Promotes EMT by Targeting miR-204-5p/SMAD4 in Endometriosis.

Endometriosis (EMs) is a systemic and chronic disease with cancer-like feature, namely, distant implantation, which caused heavy healthy burden of nearly 200 million females. LncRNAs have been proved as new modulators in epithelial-mesenchymal transition (EMT) and EMs. Quantitative real-time PCR was conducted to measure the expression level of long intergenic non-protein coding RNA, regulator of reprogramming (Linc-ROR), and miR-204-5p in ectopic endometrium (n = 25), eutopic endometrium (n = 20), and natural control endometrium (n = 22). Overexpression of Linc-ROR, knockdown or overexpression of miR-204-5p in End1/E6E7 and Ishikawa cells, was conducted to detect the function of Linc-ROR and miR-204-5p in EMs. Furthermore, luciferase reports were used to confirm the combination of Linc-ROR and miR-204-5p and the combination between miR-204-5p and SMAD4. Cell-Counting Kit-8, EdU assay, transwell assays, and Western blotting were used to detect the function of Linc-ROR and miR-204-5p in EMs cancer-like behaviors and EMT process. Linc-ROR was up-regulated in ectopic endometrium. Overexpressed Linc-ROR promotes cell proliferation, invasion, and EMT process. Linc-ROR regulated the EMT process, cellular proliferation, and invasion of EMs via binding to miR-204-5p. In addition, overexpression of Linc-ROR up-regulated SMAD4, a target protein of miR-204-5p, with which regulated EMT process and cancer-like behaviors in EMs together. Linc-ROR/miR-204-5p/SMAD4 axis plays a vital role in regulation EMT process in EMs, which might become a novel therapeutic targets and powerful biomarkers in EMs therapy.

Borneol-driven meningeal lymphatic drainage clears amyloid-ß peptide to attenuate Alzheimer-like phenotype in mice.

Rationale: The accumulation and clearance of amyloid-ß (Aß) peptides play a crucial role in the pathogenesis of Alzheimer's disease (AD). The (re)discovery of meningeal lymphatic vessels in recent years has focused attention on the lymphatic clearance of Aß and has become a promising therapeutic target for such diseases. However, there is a lack of small molecular compounds that could clearly regulate meningeal lymphatic drainage to remove Aß from the brain. Methods: We investigated the effect of borneol on meningeal lymphatic clearance of macromolecules with different molecular weights (including Aß) in the brain. To further investigate the mechanism of borneol regulating meningeal lymphatic drainage, immunofluorescence staining, western blotting, ELISA, RT-qPCR, and Nitric Oxide assay kits were used. The cognitive function of AD mice after borneol treatment was evaluated using two behavioral tests: open field (OF) and Morris water maze (MWM). Results: This study discovered that borneol could accelerate the lymphatic clearance of Aß from the brain by enhancing meningeal lymphatic drainage. Preliminary mechanism analysis revealed that borneol could improve the permeability and inner diameter of lymphatic vessels, allowing macromolecules to drain into the cervical lymph nodes (CLNS) and then be transported to the lymphatic circulation. To speed up the clearance of macromolecules, borneol also stimulated lymphatic constriction by lowering the level of nitric oxide in the meninges. In addition, borneol stimulated lymphangiogenesis by increasing the levels of FOXC2, VEGFC, and LYVE-1 in the meninges, which promoted the clearance rates of macromolecules. Borneol improved meningeal lymphatic clearance not only for Aß but also for other macromolecular polymers (molecular weight in the range of 2 KD - 45 KD. Borneol ameliorated cognitive deficits and alleviated brain Aß burden in Aß-injected mice. Conclusions: Our findings not only provide a strategy to regulate lymphatic clearance pathways of macromolecules in the brain, but also new targets and ideas for treating neurodegenerative diseases like AD. Furthermore, our findings indicate that borneol is a promising therapeutic drug for AD.

Energetic evaluation of phenol wastewater treatment by reverse electrodialysis reactor using different anodes.

Efficient electrode materials are essential to convert salinity gradient energy into oxidative degradation energy and electrical energy by reverse electrodialysis reactor (REDR). In this context, comparative experiments of REDR using different anodes (Ti/IrO2-RuO2, Ti/PbO2 and Ti/Ti4O7) were conducted. The effects of output current and electrode rinse solution (ERS) flowrate on mineralization efficiency and energy output were discussed. Results demonstrated that the COD removal rate(ηCOD) rose almost linearly with output current and ERS flowrate when using Ti/Ti4O7 anode, but excessive operating conditions caused a slow increase or even decrease of ηCOD when using Ti/IrO2-RuO2 or Ti/PbO2 anodes. The order of electrode system potential loss (Eele) for the three anodes was Ti/Ti4O7> Ti/PbO2> Ti/IrO2-RuO2. High Eele was beneficial to ηCOD but had a negative effect on the net output power (Pnet) of REDR. Regardless of the applied anodes, increasing the current and decreasing the ERS flowrate was detrimental to Pnet due to higher Eele. Based on these findings, four energy efficiency parameters were defined to evaluate energy recovery from multiple perspectives by linking energy output with mineralization capacity. They were electrode efficiency (ηele), energy efficiency (EE), general current efficiency (GCE) and energy consumption (EC), respectively. Results showed that REDR with Ti/Ti4O7 anodes and suitable operating conditions achieved the optimal energy indicators and mineralization efficiency, which provided an efficient and economical option for wastewater treatment and energy recovery.

A comprehensive pan-cancer analysis on the immunological role and prognostic value of TYMP in human cancers.

Background: The TYMP gene encodes an important nucleoside metabolism enzyme which is a rate-limiting enzyme for chemotherapeutic drug metabolism. Previous studies have shown that TYMP is highly expressed in many different tumors, promoting invasiveness and progression, and that it helps to predict the response to chemotherapeutic drugs. However, the role of TYMP in tumor immunity and prognosis remains largely unclear. The purpose of this pan-cancer analysis was to acquire more data on the function of TYMP function and its clinical significance. Methods: To access the TYMP expression, we accessed datasets from The Cancer Genome Atlas (TCGA), Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA), Cancer Cell Line Encyclopedia (CCLE) databases, and analyzed its differential expression between paired tumor and normal samples. We employed PrognoScan and Kaplan-Meier plotter for survival analyses. TYMP mutations were analyzed using cBioPortal. Correlations of TYMP with tumor stage, tumor mutational burden (TMB), microsatellite instability (MSI), immune checkpoint genes (ICGs), and immune cell infiltration were estimated via bioinformatics tools and methods. The CellMiner database was used to predict drug response. Gene set enrichment analysis (GSEA) was applied to explore the biological functions of TYMP in different tumors. Results: Our results indicated that TYMP was overexpressed and also significantly associated with a worse prognosis in several human cancers, such as kidney clear cell carcinoma (KIRC) and lower grade glioma (LGG). TYMP was also associated with TMB, MSI, and ICGs across a variety of malignancies. TYMP was most significantly correlated with immune cell infiltration in five tumors, namely, breast cancer (BRCA), cervical cancer (CESC), KIRC, skin cutaneous melanoma (SKCM), and stomach adenocarcinoma (STAD). Moreover, TYMP expression predicted sensitivity to chemotherapy drugs and also influenced relevant biological pathways, according to enrichment analysis. Conclusions: According to the results of this comprehensive analysis, TYMP is associated with prognosis and tumor immunology, which might make it be a potential therapeutic target for cancer treatment.

In situ gelation strategy based on ferrocene-hyaluronic acid organic copolymer biomaterial for exudate management and multi-modal wound healing.

Exudate management remains a major concern in slow or non-healing wound management. Therefore, there is a need to devise a massive exudate-absorbing, exudate-locking, and stable extracellular matrix structure-maintaining functional wound dressing. Inspired by metal-organic frameworks, we chemically introduced sandwich ferrocene (Fc) into hyaluronic acid (HA) to fabricate an innovative metal Fc-HA organic copolymer (FHoC) as the skeleton material for in situ gelation, which was then gently compressed into a pre-hydrogel patch (FHoCP). Fc promoted the rearrangement of polymer chains to form additional microcrystalline and hydrophobic regions, which improved hydrogel transition and the exudate-locking ability. Thus, the simple composition FHoCP(5) absorbed 150 times its weight of water and maintained a firm three-dimensional network, which contributed to reducing inflammation and acted as a physical barrier against hemostasis and anti-bacterial invasion. Meanwhile, multi-modal processes, including fibroblast migration, angiogenesis, and antibacterial effects, were integrated into the gelled FHoCP(5) guided by Fe to promote wound healing. This study suggested that FHoC biomaterial could accelerate the closure of chronic wounds. We believe that this unique FHoCP(5)-based in situ gelation strategy could provide a solid drug-loaded scaffold for cell or adjunctive drug therapies, which holds great potential for the development of multifunctional biomaterials. STATEMENT OF SIGNIFICANCE: Hydrogels that absorb excessive exudates while maintaining stable ECM-like network as well as exert multimodal wound healing activities are ideal dressings for accelerating chronic wound contraction. Herein, we reported an innovative metal ferrocene-hyaluronic acid organic copolymer patch (FHoCP) and FHoCP-mediated in situ gelation strategy. Ferrocene (Fc) induced in situ gelation by promoting polymer chain rearrangement, acting as a physical barrier for hemostasis and anti-bacterial invasion, and absorbing massive exudates, resulting in reducing delayed inflammation. As the structural core, rigid Fc enhanced the stability of the hydrogel backbone, and hydrophobic Fc improved fibroblast migration. In addition, Fe2+ chemically inhibited bacteria and increased angiogenesis. These results indicated the potential of FHoCP-based hydrogel for application in clinical skin reconstruction.

Menthol nanoliposomes enhanced anti-tumor immunotherapy by increasing lymph node homing of dendritic cell vaccines.

Menthol, a cyclic terpene alcohol, plays a critical role in overcoming the blood-brain barrier and stratum corneum barrier. Herein, we innovatively propose a menthol nanoliposome (Men-nanoLips) that can dramatically increase lymph node accumulation of the dendritic cell (DC)-based anti-tumor vaccines. Specifically, Men-nanoLips efficiently enhanced lymphatic endothelial cell (EC) barrier permeability by reducing the expression of tight junction proteins. And interestingly, Men-nanoLips not only up-regulated the expression of CCR7 in DCs but also increased the secretion of CCL21 in lymphatic ECs. Moreover, Men-nanoLips promoted DC vaccine maturation as evidenced by increasing the expression of costimulatory molecules and up-regulating the pseudopodia-like protein. With those complementary mechanisms provided by Men-nanoLips, the number of the B16 whole-tumor cell lysate-loaded DCs that target the draining LN enhanced remarkably and significantly boosted the treatment efficacy of DC anti-tumor vaccines. Therefore, we concluded that Men-nanoLips could be instructive for increasing LN homing of DC vaccines.

Comprehensive multiomics analysis of cuproptosis-related gene characteristics in hepatocellular carcinoma.

Background: The mechanism of copper-induced cell death, which is called cuproptosis, has recently been clarified. However, the integrated role of cuproptosis-related genes in hepatocellular carcinoma (HCC) and its relationship with immune characteristics are still completely unknown. Methods: In this study, the expression, genetic, and transcriptional regulation states of 16 cuproptosis-related genes in HCC were systematically investigated. An unsupervised clustering method was used to identify distinct expression patterns in 370 HCC patients from the TCGA-HCC cohort. Differences in functional characteristics among different expression clusters were clarified by gene set variation analysis (GSVA). The abundances of immune cells in each HCC sample were calculated by the CIBERSORT algorithm. Next, a cuproptosis-related risk score was established based on the significant differentially expressed genes (DEGs) among different expression clusters. Results: A specific cluster of HCC patients with poor prognosis, an inhibitory immune microenvironment, and high expression levels of immune checkpoint molecules was identified based on the expression of the 16 cuproptosis-related genes. This cluster of patients could be well-identified by a cuproptosis-related risk score system. The prognostic value of this risk score was validated in the training and two validation cohorts (TCGA-HCC, China-HCC, and Japan-HCC cohorts). Moreover, the overall expression status of the cuproptosis-related genes and the genes used to establish the cuproptosis-related risk score in specific cell types of the tumor microenvironment were preliminarily clarified by single-cell RNA (scRNA) sequencing data. Conclusion: These results indicated that cuproptosis-related genes play an important role in HCC, and targeting these genes may ameliorate the inhibitory immune microenvironment to improve the efficacy of immunotherapy with immune checkpoint inhibitors (ICIs).

Identification of the immune subtype of ovarian cancer patients by integrated analyses of transcriptome and single-cell sequencing data.

Ovarian cancer (OC) is one the most life-threatening cancers affecting women's health worldwide. Immunotherapy has become a promising treatment for a variety of cancers, but the therapeutic effects in OC remain limited. In this study, we constructed a macrophage risk score (MRS) based on M1 and M2 macrophages and a gene risk score (GRS) based on the prognostic genes associated with MRS. Next, cell-cell communication analysis was performed using single-cell RNA (scRNA) sequencing data. Survival status and immune characteristics were compared between the high- and low-score groups separated by MRS or GRS. Our results suggested that MRS and GRS can identify the immune subtypes of OC patients with better overall survival (OS) and inflammatory immune microenvironment. Moreover, M1 and M2 macrophages may affect the prognosis of OC patients through signal communication with CD8 T cells. Finally, functional differences between the two groups separated by GRS were elucidated. Taken together, this study constructed two useful models for the identification of immune subtypes in OC, which has a better prognosis and may have a sensitive response to immune checkpoint inhibitors (ICIs). The hub genes for the construction of GRS may be potential synergetic targets for immunotherapy in OC patients.

Electrochemical removal of synthetic methyl orange dyeing wastewater by reverse electrodialysis reactor: Experiment and mineralizing model.

In this paper, the synthetic methyl orange (MO) dyeing wastewater treated by a reverse electrodialysis reactor (REDR) with 40 member pairs was investigated first. The boron-doped diamond (BDD) and carbon felt were adopted as an anode and a cathode in the REDR. The influences of operation parameters on the chemical oxygen demand (COD) removal efficiency were detected and explored. Then, a mathematical model of organic mineralizing was developed for the REDR to predict the variation of COD removal efficiency with treating time under the different operation conditions. Finally, the energy consumption of the wastewater treated by the REDR was analyzed. The results showed that raising the working fluid flowing velocity and electrode rinse solution flowrate improved the COD removal efficiency and instantaneous current efficiency (ICE), and reduced the total energy consumption (TEC) of the REDR. Raising the initial MO concentration could significantly reduce the TEC despite the COD removal efficiency being near. Since the main energy consumed by the REDR was salinity gradient energy (SGE) from waste heat conversion or the natural environment, the energy cost of REDR treating wastewater has been reduced significantly.

Identification of two immune-related risk score signatures through integrated analysis of multi-omics data in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. Immunotherapy has become a major treatment for advanced HCC, but the therapeutic effects remain unsatisfactory. In this study, we constructed an immune cell risk score (ICS) and an immune cell-related gene risk score (ICRGS) for the prognosis prediction of HCC through integrated analysis of bulk and single-cell RNA (scRNA) sequencing data. These two risk score signatures both showed good predictive values in the training and validation cohorts. The potential interactions among these prognostic immune cell types were elucidated by cell-cell communication analysis. The results of enrichment analysis and gene set enrichment analysis (GSEA) of the prognostic genes showed that metabolic-related processes were involved in the immune response of HCC. Furthermore, the results of correlation analyses further confirmed the hub genes that were strongly correlated with immune cells. Finally, potential therapeutic drugs targeting these hub genes were screened by CellMiner based on NCI-60 cell line set. Taken together, two useful models for the prognosis prediction of HCC patients were constructed in this study. The functional differences between the two groups of HCC patients separated by ICS or ICRGS provide fundamental knowledge for finding synergistic therapeutic targets for HCC immunotherapy.

Effects of CDKN2B-AS1 on cellular proliferation, invasion and AKT3 expression are attenuated by miR-424-5p in a model of ovarian endometriosis.

RESEARCH QUESTION: Endometriosis is a common and complicated gynaecologic disease. Long non-coding RNA CDKN2B-AS1 plays a crucial role in the development and progression of several cancers. Whether CDKN2B-AS1 contributes to endometriosis, however, remains unknown. DESIGN: Cellular proliferation, invasion and DNA synthesis abilities were assessed by CCK8, transwell and 5-ethynyle-2'-deoxyuridine assays. The expression of epithelial-mesenchymal transition markers and three isoforms of AKT was detected using Western blot. Real-time polymerase chain reaction was used to determine the relative expression levels of CDKN2B-AS1 and candidate miRNAs in ectopic, eutopic endometria and normal endometrial tissues. The relationship between CDKN2B-AS1 and miRNA was determined by luciferase reporter assays. RESULTS: The relative expression level of CDKN2B-AS1 was up-regulated in eutopic and ectopic endometria. In endometrial stromal cells and Ishikawa cells, CDKN2B-AS1 overexpression promoted cellular proliferation and invasion, and increased the protein expression of vimentin but decreased the expression of E-cadherin. miR-424-5p was confirmed the target of CDKN2B-AS1 through bioinformatics tools and luciferase reporter assays. In addition, the enhanced effect of cellular phenotype of CDKN2B-AS1 overexpression was significantly attenuated by miR-424-5p overexpression. Furthermore, miR-424-5p was able to directly target AKT3 through luciferase reporter assay. Mechanistically, CDKN2B-AS1 acts as a ceRNA by sponging miR-424-5p and targets AKT3. CONCLUSIONS: The cellular mechanism of CDKN2B-AS1 in endometriosis was confirmed; CDKN2B-AS1 may be a potential target for ovarian endometriosis therapy.

Effects of exogenous melatonin on sleep quality and menopausal symptoms in menopausal women: a systematic review and meta-analysis of randomized controlled trials.

IMPORTANCE: Because of the bothersome symptoms during women's menopausal period and the severe side effects of hormone therapy, it is meaningful to find new breakthroughs in improving menopausal women's quality of life. OBJECTIVE: We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) evaluating melatonin intake on the improvement of sleep quality, general menopausal symptom, mood states, as well as interaction of estradiol levels and body mass index (BMI) in menopausal women. EVIDENCE REVIEW: We used the search terms "melatonin" together with "menopause" or "post-menopause" or "peri-menopause" in multiple databases online including PubMed, Web of Science, Embase, Clinical trial, Cochrane Library, and China National Knowledge Infrastructure from the first publication year to October 2020. Interesting data included characteristics of the study design, study participants, intervention, and outcome measures. Risk of biases in RCTs was evaluated with the Cochrane tool. Fixed-effect models and random-effect models were used for meta-analysis according to heterogeneity. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed in our study. FINDINGS: Eight cohorts (n = 812) evaluating the effects of melatonin in menopausal women were included. Melatonin was used in every study with differences existing in dose (1 mg - 5 mg) and duration (3 to 12 mo). Improved physical symptoms (standard mean difference [SMD] -0.376; 95% CI, -0.599 to -0.153, P = 0.001) merged in four RCTs. Melatonin treatment resulted in no benefits to sleep quality (SMD -0.659; 95% CI, -1.535 to 0.217, P = 0.141) and general menopause symptoms (SMD -0.625; 95% CI, -1.354 to 0.105, P = 0.093) in four and three RCTs, respectively. More specifically, melatonin did not solve the psychological (SMD -0.026; 95% CI, -0.372 to 0.321, P = 0.884, I2 = 70.3%), sexual (SMD -0.661; 95% CI, -1.416 to 0.093, P = 0.086) and vasomotor (SMD -0.256; 95% CI, -0.701 to 0.188, P = 0.258) issues. No significant changes were observed in anxiety (SMD 0.018; 95% CI, -0.519 to 0.556, P = 0.946), depression (SMD 0.133; 95% CI, -0.435 to 0.702, P = 0.646), BMI (weighted mean difference 0.029 kg/m2; 95% CI, -0.183 to 0.240, P = 0.790) or estradiol levels (weighted mean difference 0.016 pg/mL; 95% CI, -1.220 to 1.252, P = 0.980). CONCLUSIONS: Melatonin seems to improve physical symptoms in menopausal women, but the general menopausal symptoms, sleep quality, mood state, estradiol levels, and BMI did not improve under melatonin intervention. However, multiple large-scale clinical randomized trials are needed to validate our conclusions.

Sentinel lymph node biopsy in early stage cervical cancer: A meta-analysis.

BACKGROUND: The aim of this study was to determine the specific side detection rate of the sentinel lymph node biopsy and the accuracy in predicting lymph node metastasis in early stage cervical cancer. METHODS: A systematic search of databases was performed from the inception of the databases to 27 June 2020. Studies of cervical cancer patients with FIGO stage FIGO ⅠA~ⅡB, evaluating the sentinel lymph node biopsy with blue dye, technetium 99, combined technique (blue dye with technetium 99) or indocyanine green with a reference standard of systematic pelvis lymph node dissection or clinical follow-up were included. Stata12.0 and Meta-Disc 1.4 were used for the meta-analysis. RESULTS: Of 2825 articles found, 21 studies (2234 women) were eventually included. Out of 21 studies, 20 met the detection rate evaluation criteria and six were included for sensitivity meta-analysis. Due to heterogeneity, it was inappropriate to pool all studies. The pooled specific side detection rates were 85% in tumors up to 2 cm, 67% in tumors over 2 cm, 75.2% for blue dye, 74.7% for technetium 99, 84% for combined technique, and 85.5% for indocyanine green. The sentinel lymph node biopsy had a pooled specific side sensitivity of 88%. Adverse effects of sentinel lymph node biopsy appear minimal for most patients and are mainly related to the injection of blue dye. CONCLUSIONS: Sentinel lymph node biopsy using a tracer with a high detection rate and ultrastaging is highly accurate and reliable when limited to seriously selected patients, with satisfactory bilateral lymph node mapping and where enough cases for learning curve optimization exist. Indocyanine green sentinel lymph node mapping seems to be a superior sentinel lymph node mapping technique compared to other methods at present.

LINC01018 and SMIM25 sponged miR-182-5p in endometriosis revealed by the ceRNA network construction.

The current study intended to explore the interaction of the long non-coding RNA (lncRNA), microRNA (miRNA), and messenger RNA (mRNA) under the background of competitive endogenous RNA (ceRNA) network in endometriosis (EMs). The differentially expressed miRNAs (DEmiRs), differentially expressed lncRNA (DELs), and differentially expressed genes (DEGs) between EMs ectopic (EC) and eutopic (EU) endometrium based on three RNA-sequencing datasets (GSE105765, GSE121406, and GSE105764) were identified, which were used for the construction of ceRNA network. Then, DEGs in the ceRNA network were performed with Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and protein-protein interaction (PPI) analysis. Besides, the DEmiRs in the ceRNA network were validated in GSE124010. And the target DELs and DEGs of verified DEmiRs were validated in GSE86534. The correlation of verified DEmiRs, DEGs, and DELs was explored. Moreover, gene set enrichment analysis (GSEA) was applied to investigate the function of verified DEmiRs, DEGs, and DELs. Overall, 1352 DEGs and 595 DELs from GSE105764, along with 27 overlapped DEmiRs between GSE105765 and GSE121406, were obtained. Subsequently, a ceRNA network, including 11 upregulated and 16 downregulated DEmiRs, 7 upregulated and 13 downregulated DELs, 48 upregulated and 46 downregulated DEGs, was constructed. The GO and KEGG pathway analysis showed that this ceRNA network probably was associated with inflammation-related pathways. Furthermore, hsa-miR-182-5p and its target DELs (LINC01018 and SMIM25) and DEGs (BNC2, CHL1, HMCN1, PRDM16) were successfully verified in the validation analysis. Besides, hsa-miR-182-5p was significantly negatively correlated with these target DELs and DEGs. The GSEA analysis implied that high expression of LINC01018, SMIM25, and CHL1, and low expression of hsa-miR-182-5p would activate inflammation-related pathways in endometriosis EU samples.LINC01018 and SMIM25 might sponge hsa-miR-182-5p to upregulate downstream genes such as CHL1 to promote the development of endometriosis.

Exploring diagnostic m6A regulators in endometriosis.

Endometriosis is an estrogen-dependent inflammatory disorder, usually causing infertility, pelvic pain, and ovarian masses. This study intended to investigate the implication of N6-methyladenosine (m6A) regulators in endometriosis. We acquired 34 normal, 127 eutopic, and 46 ectopic, samples of endometrium from the Gene Expression Omnibus (GSE7305, GSE7307, GSE51981) database and the Array-express (E-MTAB-694) database. These samples were then used to profile the expression of 20 m6A regulators in endometriosis. The results indicated that most dysregulated (19/20) m6A regulators were significantly downregulated in eutopic vs. normal endometrium and also significantly downregulated in ectopic vs. eutopic endometrium. Several dysregulated m6A regulators were common to both contrast matrices: METTL3, YTHDF2, YTHDF3, HNRNPA2B1, HNRNPC, and FTO. Both HNRNPA2B1 and HNRNPC were associated with the severity of endometriosis in eutopic samples, and also exhibited diagnostic potential for endometriosis. HNRNPA2B1 and HNRNPC may influence immune pathways and the infiltration of immune cells in endometriosis. Abnormalities in the gene transcription factors network associated with endometriosis might affect the expression of HNRNPA2B1 and HNRNPC. In conclusion, we observed significant dysregulation of m6A regulators in endometriosis, and found that HNRNPA2B1 and HNRNPC might correlate with the immune response and serve as useful diagnostic biomarkers for endometriosis.

Common and specific gene signatures among three different endometriosis subtypes.

AIMS: To identify the common and specific molecular mechanisms of three well-defined subtypes of endometriosis (EMs): ovarian endometriosis (OE), peritoneal endometriosis (PE), and deep infiltrating endometriosis (DIE). METHODS: Four microarray datasets: GSE7305 and GSE7307 for OE, E-MTAB-694 for PE, and GSE25628 for DIE were downloaded from public databases and conducted to compare ectopic lesions (EC) with eutopic endometrium (EU) from EMs patients. Differentially expressed genes (DEGs) identified by limma package were divided into two parts: common DEGs among three subtypes and specific DEGs in each subtype, both of which were subsequently performed with the Kyoto Encyclopedia of Genes (KEGG) pathway enrichment analysis. The protein-protein interaction (PPI) network was constructed by common DEGs and five hub genes were screened out from the PPI network. Besides, these five hub genes together with selected interested pathway-related genes were further validated in an independent OE RNA-sequencing dataset GSE105764. RESULTS: A total of 54 EC samples from three EMs subtypes (OE, PE, DIE) and 58 EU samples were analyzed, from which we obtained 148 common DEGs among three subtypes, and 729 specific DEGs in OE, 777 specific DEGs in PE and 36 specific DEGs in DIE. The most enriched pathway of 148 shared DEGs was arachidonic acid (AA) metabolism, in which most genes were up-regulated in EC, indicating inflammation was the most common pathogenesis of three subtypes. Besides, five hub genes AURKB, RRM2, DTL, CCNB1, CCNB2 identified from the PPI network constructed by 148 shared DEGs were all associated with cell cycle and mitosis, and down-regulated in EC, suggesting a slow and controlled proliferation in ectopic lesions. The KEGG pathway analysis of specific DEGs in each subtype revealed that abnormal ovarian steroidogenesis was a prominent feature in OE; OE and DIE seems to be at more risk of malignant development since both of their specific DEGs were enriched in the pathways in cancer, though enriched genes were different, while PE tended to be more associated with dysregulated peritoneal immune and inflammatory microenvironment. CONCLUSION: By integrated bioinformatic analysis, we explored common and specific molecular signatures among different subtypes of endometriosis: activated arachidonic acid (AA) metabolism-related inflammatory process and a slow and controlled proliferation in ectopic lesions were common features in OE, PE and DIE; OE and DIE seemed to be at more risk of malignant development while PE tended to be more associated with dysregulated peritoneal immune and inflammatory microenvironment, all of which could deepen our perception of endometriosis.